2. Academic Validation
  3. Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain

  • J Med Chem. 2018 Jun 14;61(11):4810-4831. doi: 10.1021/acs.jmedchem.7b01826.
Thilo Focken 1,  Sultan Chowdhury 1,  Alla Zenova 1,  Michael E Grimwood 1,  Christine Chabot 2,  Tao Sheng 1,  Ivan Hemeon 1,  Shannon M Decker 1,  Michael Wilson 1,  Paul Bichler 1,  Qi Jia 1,  Shaoyi Sun 1,  Clint Young 1,  Sophia Lin 1,  Samuel J Goodchild 1,  Noah G Shuart 1,  Elaine Chang 1,  Zhiwei Xie 1,  Bowen Li 1,  Kuldip Khakh 1,  Girish Bankar 1,  Matthew Waldbrook 1,  Rainbow Kwan 1,  Karen Nelkenbrecher 1,  Parisa Karimi Tari 1,  Navjot Chahal 1,  Luis Sojo 1,  C Lee Robinette 1,  Andrew D White 3,  Chien-An Chen 3,  Yi Zhang 3,  Jodie Pang 2,  Jae H Chang 2,  David H Hackos 2,  J P Johnson Jr 1,  Charles J Cohen 1,  Daniel F Ortwine 2,  Daniel P Sutherlin 2,  Christoph M Dehnhardt 1,  Brian S Safina 2
Affiliations

Affiliations

  • 1 Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way , Burnaby , BC V5G 4W8 , Canada.
  • 2 Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 3 Chempartner , Building No. 5, 998 Halei Rd. , Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203 , China.
PMID: 29737846 DOI: 10.1021/acs.jmedchem.7b01826
Abstract

The Sodium Channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

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